We have initiated a series of investigations to determine the impact of some neuroendocrine challenges on the immune system. Two pharmacologic stress tests were performed on rats and the acute (4h) effect on splenic lymphocytes was determined. We have observed that the B-adrenergic agonist, isoproterenol, suppressed responses of lymphcyte to mitogen stimulation. This inhibitory effect of isoproterenol on lymphocytes is not due to direct effects of isoproterenol, but may be directly related to the presence of the adrenal gland (adrenalectomized animals injected with isoproterenol did not exhibit suppression of lymphocyte activity). Further in vitro studies demonstrated a direct suppressive effect of the glucocorticoid agonist, dexamethasone and this suppressive effect may be mediated through the phosphatidylinositol cycle (the phorbol ester, PMA, a stimulator of protein kihase C, inhibits lymphocyte activity.) The second stress test was insulin induced hypoglycemia. Lowering of blood glucose over a 4-h period caused a marked suppression in lymphocyte activity. Thus, the acute effect of pharmacologic stress is to inhibit lymphocyte activity. Studies are in progress to determine the effect of chronic pharmacologic stress on lymphocyte activity.